The responses of neurons in the visual cortex can undergo experience-dependent changes, particularly during early life. Abnormal experience during this "critical period" can permanently impair vision (e.g. amblyopia) due to improper cortical wiring. This demonstrates the importance of experience-dependent synaptic plasticity. Activation of NMDA-type glutamate receptors (NMDARs) is required for many forms of experience-dependent plasticity. While NMDARs are traditionally thought to exert their influences postsynaptically, a surprising recent finding is that NMDARs are also expressed presynaptically early in development. These presynaptic receptors are involved in regulating neurotransmitter release and long-term depression (LTD) of synaptic strength. The relative contribution of pre- and postsynaptic NMDARs during animal development remains unknown, yet this information is crucial to understanding how fundamental mechanisms of synaptic transmission and plasticity change at the onset of the critical period. Our data demonstrate, for the first time, an abrupt loss of presynaptic NMDAR function that coincides with the onset of the critical period for visual cortical plasticity. Here we will examine the central hypothesis that presynaptic NMDARs are involved in the induction of LTD before the onset of the critical period, but their experience- dependent loss triggers a new LTD induction mechanism to emerge. We will use electrophysiological and anatomical approaches in mice to address three crucial questions. (1) What allows presynaptic NMDARs to function, and what underlies their developmental loss? (2) Does experience modify the function of presynaptic NMDARs in an age-dependent mariner? (3) How do presynaptic NMDARs contribute to synaptic transmission and plasticity? Because LTD of excitatory synapses is one mechanism by which visual responsiveness may be lost due to aberrant visual experience, a particularly important goal is to elucidate the involvement of presynaptic NMDARs in LTD and how this might differ during the critical period. By demonstrating that both pre- and postsynaptic NMDARs contribute to the expression of synaptic plasticity, and that their relative roles shift over development, our findings are expected to define a novel, and perhaps general, property of synaptic plasticity in emerging cortical circuits. Relevance to public health: Amblyopia is the most common form of visual impairment during childhood and, if left untreated, is permanent. The weakening of synaptic inputs driven by the deprived eye is thought to underlie the visual deficits. Accordingly, knowledge of the fundamental mechanisms of synaptic weakening will lead to rational strategies for preventing the deleterious consequences of visual deprivation and will increase our understanding of normal visual cortical development. [unreadable] [unreadable] [unreadable]